Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: Focus on myeloperoxidase.
Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: Focus on myeloperoxidase.
复制标题
DOI：
10.3109/10715762.2010.521154
复制
发表时间：
2011-02
影响因子：
3.3
通讯作者：
Eiserich JP
中科院分区：
文献类型：
--
作者：
Vasu VT;de Cruz SJ;Houghton JS;Hayakawa KA;Morrissey BM;Cross CE;Eiserich JP
髓过氧化物酶（MPO）催化的中性粒细胞依赖性反应被认为在囊性纤维化（CF）的肺病理生物学中起重要作用。雾化的硫醇抗氧化剂如谷胱甘肽（GSH）和N-乙酰半胱氨酸（NAC）目前被用作治疗剂以改变CF呼吸道氧化过程。我们假设CF气道衬里液中的MPO可能是这种治疗的靶点。21例成人CF患者痰液中MPO活性与肺功能（FEV 1）呈负相关。相反，全身性炎症（通过血浆C反应蛋白评估）与肺功能无关。体外研究表明，GSH和NAC有效地清除痰中的N-氯胺，并抑制痰MPO活性，其效力精确地依赖于MPO活性水平。详细的动力学分析表明，NAC和GSH通过不同的机制抑制MPO。GSH可抑制HBE 1细胞中关键的促炎性转录因子NF-κB的活化。我们的研究结果表明，MPO活性及其反应产物代表了改善CF患者气道氧化应激和炎症所需的吸入硫醇抗氧化剂剂量的有用预测因子，并提供了对GSH和NAC在CF肺中给药时的抗氧化/抗炎作用机制的机械见解。
Neutrophil-dependent reactions catalyzed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. We hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV1). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum, and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key proinflammatory transcription factor NF-κB in cultured HBE1 cells was inhibited by GSH. Our findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients, and provides mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung.
登录
查看更多内容
影响因子：
24.3
作者：
De Rse, V
通讯作者：
De Rse, V
影响因子：
3.3
作者：
Cantin, AM
通讯作者：
Cantin, AM
影响因子：
7.4
作者：
Kaul, N;Forman, HJ
通讯作者：
Forman, HJ
影响因子：
15.9
作者：
CANTIN, AM;BILODEAU, G;MARTEL, M
通讯作者：
MARTEL, M
DOI：
10.1164/rccm.200308-1104oc
发表时间：
2004-04-01
影响因子：
24.7
作者：
Griese, M;Ramakers, I;Scheuch, G
通讯作者：
Scheuch, G